REGULATION OF ANTIGEN PRESENTATION BY ACIDIC PROTEASES

Project: Research project

Description

Antigens are processed by acidic proteases prior to presentation in
the context of class II histocompatibility proteins. The formation of
a trimolecular complex of processed antigen, class II proteins, and
T-cell receptor is essential for immune recognition and responses.
This study will investigate the role of acidic endosomal proteases in
antigen processing and invariant chain release from HLA class II
proteins. The coordinate regulation of these proteolytic events is
critical to antigen presentation, as invariant chain release must
occur prior to peptide antigens binding to class II proteins. In
humans, the precise enzymes which function in antigen and invariant
chain processing have not been identified nor have the factors which
regulate protease activity been defined. Immune responsiveness may be
linked to protease expression, as differences in antigen processing
have been detected among individuals. Proteolytic processing is a
prerequisite for the presentation and recognition of both foreign and
self antigens. The generation of self peptides which bind specific
class II alleles, may be a key event initiating autoimmune reactivity.
Thus, protease expression may represent a previously unrecognized
genetic factor in susceptibility to autoimmune disorders. The long-term goals of this research program are to define the
critical intracellular events which regulate antigen presentation and
determine how protease expression controls responses to foreign and
self antigens in humans. For these purposes, antigen processing and
presentation will be studied in human B-cell lines which display high
levels of class II proteins. In B-cells both invariant chain release
from class II proteins and antigen processing may occur in endosomes.
Specifically, this proposal will: 1) Determine if antigenic peptides
are generated by endosomal proteases and how changes in endosomal
protease activity modulate antigen presentation; 2) Evaluate if
polymorphic class II antigens found in endosomes influence processing
and the formation of antigenic determinants; 3) Investigate the
requirement for aspartyl proteases, such as cathepsin D in the
processing of antigens and invariant chain through the generation of
mutant cell lines. A combination of cell biological as well as
molecular and cellular immunological approaches will be employed for
each of these specific aims.
StatusFinished
Effective start/end date7/1/936/30/03

Funding

  • National Institutes of Health: $245,467.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $136,638.00
  • National Institutes of Health: $224,983.00
  • National Institutes of Health: $252,260.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $233,003.00
  • National Institutes of Health: $72,369.00

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Antigen Presentation
Peptide Hydrolases
Epitopes
Histocompatibility Antigens Class II
Antigens
Proteins
Endosomes
T-Lymphocytes
Immunodominant Epitopes
T-Cell Antigen Receptor
B-Lymphocytes
Autoimmunity
Aspartic Acid Proteases
Peptides
Cell Line
Cathepsin D
Histocompatibility
Research

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)